He made his stage debut in 1922 in the farcical play Tons of Money on the Isle of Wight and appeared in the West End for the first time in 1925 in Beggar on Horseback. Hyde-White's early film career began in 1934 with Josser on the Farm, and he later added the hyphen to his surname. He gained recognition in British films during the 1950s, appearing in notable works such as The Third Man (1949), Carry On Nurse (1959), and On the Double (1961). His stage credits include performances opposite Laurence Olivier and Vivien Leigh in Caesar and Cleopatra and Antony and Cleopatrain 1951. He also starred in the Broadway production of The Jockey Club Stakes in 1973, earning a Tony Award nomination for Best Actor in a Play.

In 1964, Hyde-White achieved international fame with his portrayal of Colonel Hugh Pickering in the film adaptation of the musical My Fair Lady. Directed by George Cukor and starring Audrey Hepburn as Eliza Doolittle and Rex Harrison as Henry Higgins, the film was a critical and commercial success, winning eight Academy Awards, including Best Picture. Hyde-White's performance as the supportive and gentlemanly phonetics expert was widely praised, contributing to the film's enduring legacy as one of the greatest movie musicals.

Hyde-White's career spanned over five decades, during which he appeared in more than 160 film and television roles. In the 1970s and 1980s, he featured in television series such as Battlestar Galactica and Buck Rogers in the 25th Century, and made guest appearances on Columbo. He also lent his voice to the BBC radio comedy The Men from the Ministry between 1962 and 1965.

Hyde-White was married twice. His first wife, Blanche Hope Aitken (professionally known as Blanche Glynne), was a Glamorgan-born British actress with whom he had one son. After her death in 1946, he married actress Ethel Drew in 1957, and they had two children, including actor Alex Hyde-White. Known for his bon vivant lifestyle, Hyde-White faced financial difficulties later in life and was declared bankrupt by the Inland Revenue in 1979. He spent his final years in the United States as a tax exile. He passed away on May 6, 1991, at the Motion Picture Country Home in Woodland Hills, California, at the age of 87. He is buried in Water Cemetery, Bourton-on-the-Water, Gloucestershire, England.

Wilfrid Hyde-White's legacy endures through his extensive body of work, characterized by his distinctive voice, impeccable comedic timing, and portrayal of dignified yet often humorous characters. His role in My Fair Lady remains a highlight of his career, showcasing his ability to bring warmth and sophistication to the screen.